AMPAR ligand discovery for Alzheimer's disease

项目摘要。AMPA受体（AMPARs）是快速多巴胺能神经传递的主要转导子 在整个中枢神经系统（CNS）中，它们控制兴奋性突触的强度并调节 长时程增强（LTP）-学习和记忆功能的基本机制。AMPAR功能障碍 与包括阿尔茨海默病（AD）在内的多种神经退行性疾病有关。因此 AMPAR的药理学调节代表了一种有吸引力的治疗方法。正电子发射断层摄影术 (PET)能够在体内定量生物化学过程，并且合适的AMPAR配体将基本上 提高我们对不同病理生理学AD下AMPAR介导的离子型谷氨酸信号的理解 条件下，否则无法通过离体（破坏性）分析。活体脑内AMPAR的PET定量研究 将提供新的AMPAR靶向药物的分布、靶向接合和剂量占用的评估。 神经治疗学迄今为止，还没有成功的例子被证明可以对GluA 2特异性AMPAR进行成像， 药物发现和临床应用，代表了我们在体内研究该靶点的能力的显著不足。因此，我们认为， 我们建议开发一种新的PET配体，可以填补这一空白，作为第一个平移成像工具。 我们是第一个开发AMPAR GluA 2特异性配体的团队，包括[11 C]AMPA-1905（由美国生物技术研究所开发）。 2020年）。然而，由于体内的边缘结合特异性，该配体被中断。在我们的第二代， 我们鉴定了一个先导分子AMPA-2076，它显示出高的结合亲和力和优异的选择性， iGlu受体。合成了AMPA-2076的18F-同位素体，并进行了初步的PET成像研究 我们已经克服了GluA 2特异性AMPAR配体开发的两个主要障碍， 在脑中的体内稳定性显著提高和2）高靶特异性。虽然AMPA-2076是一个有前途的 开发新的GluA 2靶向AMPAR配体的先导分子，进一步优化以改善结合 寻求具有适当脑动力学的特异性用于翻译跨物种成像研究，以实现最佳的 AMPAR（GluA 2亚基）在活体大脑中的定量，用于AD患者的药物发现和临床转化。 基于AMPA-2076作为药物化学优化的有效先导，作为具体目标，我们 将设计和制备一个适合用11 C或18F标记的GluA 2特异性AMPAR调节剂的集中文库， 并评估其在啮齿动物和非人类中定量AMPAR活性和药物激发期间变化的能力 灵长类动物，以及放射自显影和死后人脑组织的生物学验证。这样做的影响 工作不仅是开发第一个成功的高亲和力和选择性的AMPAR PET配体，用于研究 神经退行性疾病相关的生物学过程，而且最终，通过PET成像验证， 物种，以推进这种配体的潜在临床翻译和监测新的神经治疗剂的靶向反应 包括AD在内的神经退行性疾病

Project Summary. AMPA receptors (AMPARs) are the principle transducers of fast glutamatergic neurotransmission throughout the central nervous system (CNS), where they control the strength of excitatory synapses and modulate long-term potentiation (LTP) - a fundamental mechanism of learning and memory function. AMPAR dysfunction has been implicated in a variety of neurodegenerative diseases, including Alzheimer’s disease (AD). Therefore pharmacological modulation of AMPAR represents an attractive therapeutic approach. Positron emission tomograohy (PET) is capable of quantifying biochemical processes in vivo, and a suitable AMPAR ligand would substantially improve our understanding of AMPAR-mediated ionotropic glutamate signaling under different pathophysiological AD conditions, otherwise inaccessible by ex vivo (destructive) analysis. Quantification of AMPAR in living brain by PET would provide the assessment of distribution, target engagement and dose occupancy of new AMPAR-targeted neurotherapeutics. To date, no successful examples have been demonstrated to image GluA2-specific AMPAR for drug discovery and clinical use, representing a significant deficiency of our ability to study this target in vivo. Therefore, we propose to develop a novel PET ligand that can fill this void, as the first translational imaging tool. We are the first groups to develop AMPAR GluA2-specific ligands, including [11C]AMPA-1905 (developed by the PI in 2020). However, this ligand was discontinued due to marginal binding specificity in vivo. In our 2nd generation, we identified a lead molecule, AMPA-2076, which showed high binding affinity and excellent selectivity over all other iGlu receptors. An 18F-isotopologue of AMPA-2076 was synthesized and preliminary PET imaging studies confirmed that we have overcome two major obstacles for GluA2-specific AMPAR ligand development by achieving: 1) substantially-improved in vivo stability in the brain and 2) high target specificity. Though AMPA-2076 is a promising lead molecule for the development of new GluA2-targeted AMPAR ligands, further optimization for improved binding specificity with proper brain kinetics are sought for translational cross-species imaging studies to achieve optimal AMPAR (GluA2 subunit) quantification in the living brain for drug discovery and clinical translation for AD patients. On the basis that AMPA-2076 serves a validated lead for medicinal chemistry optimization, as specific goals, we will design and prepare a focused library of GluA2-specific AMPAR modulators amenable for labeling with 11C or 18F, and evaluate their ability to quantify AMPAR activity and changes during drug challenge in rodents and nonhuman primates, as well as autoradiography and biological validation in postmortem human brain tissues. The impact of this work is not only to develop the first successful high-affinity and selective AMPAR PET ligand for the study of neurodegenerative disease-related biological processes, but also ultimately, via PET imaging validation in higher species, to advance this ligand for potential clinical translation and monitor target response of novel neurotherapeutics for neurodegenerative diseases, including AD.